The invention relates to the new use of antiestrogens for the production of a pharmaceutical agent for treating a relative androgen deficiency in men.
In men, increasing age leads to a reduction of testicular androgen production and androgen concentration in the organism. In contrast to the situation in women, in whom estrogen production drops to castration values within a comparatively short period, this takes decades in men and involves a gradual drop. The total concentration of testosterone in the serum in the older age group is significantly reduced compared to the values in young men. Because of the increase in steroid hormone-binding globulin (SHBG) that coincides with the aging process, moreover, the proportion of free, unbound, and thus biologically active testosterone drops. In addition, the serum levels of estrogens, although they are produced from androgens by direct conversion, do not drop in the same way as a function of age. As a result, the hormonal environment is significantly altered.
In men, the hormonal environment of the sexual steroids is characterized by a significant preponderance of androgens over estrogens. While the circulating main component of androgens, testosterone, is detected in the serum in units in the range of nmol/l, the estrogen antagonist, estradiol, can be measured only in the range of pmol/l. This considerable preponderance of androgen can be detected basically in the entire late puberty period of life, but there is a clearly different intensity of this androgen dominance as a function of age. With increasing age and particularly so in those over the age of 60, there is a less pronounced emphasis of the androgen preponderance.
In older men there are relative decreases in the preponderance of testosterone by 30-50% compared to the previous values found in young men.
The relative testosterone deficiency per se can be regarded as responsible for a number of age-related disorders. Reduction of muscle mass accompanied by limitation of body performance capacity, reduction of bone density and in individual cases even osteoporosis, an increase in prostate size referred to as benign prostatic hyperplasia, reduction of libido and potency, and psycho-vegetative disorders such as depression and a decline in cognitive functions, which are disorders that are often generically referred to as Male Menopause and are caused by relative androgen deficiency in men. Libido is the desire to obtain an erection, while potency is the ability to have that erection.
It is known that in younger men, testosterone values are also effectively increased by daily treatment with antiestrogens to treat male infertility. Treatment of Male Infertility, Springer-Verlag Berlin, Heidelberg, New York 1982; Fuse, H. et al., Archives of Andrology 31 (1993) 139-145); Nonsurgical Treatment of Male Infertility, Jarow, J., Infertility in the Male, pp. 410-422. However, it has been thought that antiestrogens do not seem well suited for treatment of a relative androgen deficiency in men. Thus, for example, U.S. Pat. No. 5,861,389 proposes the use of at least one aromatase inhibitor for the production of a pharmaceutical agent for treating a relative androgen deficiency in men.
With regard to changes in cognitive function in aging males, there is a relationship between declining levels of testosterone and Alzheimer's disease. Loss of testosterone with aging can result in mental status changes such as loss of cognitive function and can worsen symptoms of Alzheimer's disease. “Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3beta but not of cyclin-dependent kinase 5 and c-Jun NH2-terminal kinase and concomitantly abolishes hyperphosphorylation of tau: Implications for Alzheimer's disease,” S. Papasozomenos and A. Shanava, Proc Natl Acad Sci U S A. 2002 Jan. 22. “Testosterone attenuates beta-amyloid toxicity in cultured hippocampal neurons,” C. Pike, Brain Res. 2001 Nov. 16; 919(1):160-5. “Testosterone reduces neuronal secretion of Alzheimer's beta-amyloid peptides,” Gouras et al, Proc Natl Acad Sci U S A. 2000 Feb. 1 vol. 97 no. 3 pp. 1202-5.
In older men, low testosterone levels is associated with obesity, upper body fat distribution and increased levels of glucose and insulin, and may worsen the symptoms and lead to the development of insulin resistance and type 2 Diabetes (Jee-Young Oh, Elizabeth Barrett-Connor, Nicole M. Wedick and Deborah L. Wingard, Endogenous Sex Hormones And The Development Of Type 2 Diabetes In Older Men And Women: The Rancho Bernardo Study, Diabetes Care, volume 25(1)55-60, January 2002.